An Open-label Study to Assess the Safety, Efficacy, and Cellular Kinetics of YTB323 in Relapsing Multiple Sclerosis

An Open-label, Multi-center, Phase 1/2 Study to Assess Safety, Efficacy, and Cellular Kinetics of YTB323 in Participants With Relapsing Multiple Sclerosis With Breakthrough Disease Activity During Previous Treatment With a Highly Efficacious Therapy

This is an open-label, multi-center, non-confirmatory study to assess the safety, efficacy, and cellular kinetics of YTB323 in approximately 28 participants with Relapsing Multiple Sclerosis (RMS) with breakthrough disease activity during previous treatment with a highly efficacious therapy (BD-HET). The study design utilizes an ascending single dose design consisting of 3 sentinel cohorts followed by an expansion cohort.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsing Multiple Sclerosis
• Intervention / Treatment: Biological: rapcabtagene autoleucel (YTB323)

Detailed Description

All participants in this study will receive YTB323. Both the participant and the study doctor will know the participant is getting YTB323. Participants will be given one dose of YTB323. Different groups of participants may receive a higher dose of YTB323, if proven to be safe for every participant at the lower dose. Participants are in this study for 2 years and will be followed for an additional 13 years in a long-term follow up study. The main question this trial is designed to answer: Is YTB323 treatment safe for participants with relapsing MS?

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Novartis Investigative Site
• France
  • Montpellier, France, 34090
    • Novartis Investigative Site
  • Nancy, France, 54035
    • Novartis Investigative Site
  • Rennes, France, 35033
    • Novartis Investigative Site
• Germany
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20132
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Córdoba, Spain, 14004
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Valencia, Spain, 46026
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent, and able to communicate well with the investigator and comply with the requirements of the study
• Adequate renal, hepatic, cardiac, hematological, and pulmonary function
• Male or female participants, ≥18 years to ≤60 years at screening, with diagnosis of RMS according to the 2017 McDonald diagnostic criteria Evidence of recent (i.e. within 1 year) breakthrough disease activity while at least 6 months on a highly efficacious therapy (any of the following): rituximab (Rituxan®), ocrelizumab (Ocrevus®), natalizumab (Tysabri®), ofatumumab (Kesimpta®), ublituximab (Briumvi®) or evidence of breakthrough disease activity within 2 years after the latest alemtuzumab infusion (Lemtrada®).

Evidence of breakthrough disease activity is defined as one or more of the following:

1. Confirmed Clinical MS relapse

2. Persistent radiological activity defined by one of the following:

   • ≥2 T1 gadolinium-enhancing lesions on a single MRI scan
   • ≥1 T1 gadolinium-enhancing lesions on two or more separate MRI scans

   • ≥2 new T2 lesions compared to a previous scan within a period ≤1 year

     • Ambulatory patients (EDSS of 3 to 6 points, inclusive assessed outside of relapse)
     • Disease duration less than 15 years
     • Participants must receive or be current on all recommended vaccinations according to institutional, local, or global guidelines for immunocompromised patients at least 6-weeks prior to lymphodepletion

Exclusion Criteria:

• Diagnosis of primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria at screening
• History of or current clinically significant CNS disease (e.g. stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS or ICANS at screening
• Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 6 months prior to screening), neurological disorders other than MS (including seizure disorders even when well controlled), psychiatric, pulmonary (including, history of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis), renal, hepatic, endocrine, metabolic (e.g. severe hypoproteinemia due to nephrotic syndrome), hematological disorders or gastrointestinal disease that, in the investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant, prior to screening
• Have donated blood or experienced a loss of blood > 400 mL within 3 months prior screening, or longer if required by local regulations
• Any prior stem cell therapy or organ transplantation or gene therapy

• Any contraindications to LP, including but not limited to:

  • Known or suspected structural abnormality of the lumbar spine that, in the opinion of the Investigator, may interfere with the performance of the LP, or increase the risk of the procedure for the participant
  • Presence of risk for increased or uncontrolled bleeding including, but not limited to, vascular abnormalities or neoplasms at or near the LP site, disorders of the coagulation cascade, platelet function, or platelet count
  • Participants on anticoagulants (e.g., warfarin) or antiplatelets [except for low-dose aspirin (100 mg/day or lower) and low-dose ibuprofen (600 mg/day or lower) which are allowable], are not eligible to participate
• Participants not willing or able to take MRI scans as per protocol. Unable to undergo MRI due to for example claustrophobia, or presents absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator)

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YTB323 Cohort 1; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 2; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 3; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion
Experimental: YTB323 Cohort 4; Participants will receive one dose of YTB323	Biological: rapcabtagene autoleucel (YTB323); CAR-T cell suspension for intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence of dose limiting toxicities (DLTs), AEs and SAEs, including changes in vital signs, electrocardiograms (ECGs), laboratory parameters, neurological status and magnetic resonance (MRI) of the brain and spinal cord qualifying and reported as AEs.	Day 1 through Year 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of Disability: Expanded Disability Status Scale (EDSS).	EDSS is used to measure the change in disability level in participants using a scale from 0 to 10. The higher the score, the greater the degree of disability.	Day 1 through Year 2
Measure of Disability: Short Form Health Survey (SF-36 v2)	The Short Form Health Survey (SF-36 v2) is a widely used and extensively studied instrument to measure health-related quality of life among healthy participants and participants with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF 36 has proven useful in monitoring general and specific populations, comparing the relative burden of different diseases, differentiating the health benefits produced by different treatments, and in screening individual participants.	Day 1 through Year 2
Measure of Disability: Timed 25 Foot Walk (T25FW)	The T25FW is a mobility test based on a timed walk of 25 feet that is administered by a trained administrator. The participant is directed to walk the clearly marked 25-foot distance as quickly as possible. Longer completion time corresponds with decreased mobility.	Day 1 through Year 2
Measure of Disability: 9 Hole Peg Test (9HPT)	The 9HPT is a finger dexterity test that is administered by a trained administrator. The participant is directed to put 9 pegs, one by one, onto and then off the holder board as quickly as possible starting with using only the dominant hand, and then repeated with the non-dominant hand. Longer completion times are associated with decreased finger dexterity.	Day 1 through Year 2
Measure of Disability: Symbol Digit Modalities Test (SDMT)	The SDMT is a timed cognition test administered by a trained administrator. The test assesses sustained attention, processing speed, visual scanning, and motor speed to determine cognitive impairment. Participants are given a coding key which contains abstract symbols that correspond to specific numbers. Participants are timed how quickly and accurately they are able to substitute the symbols for the numbers and is scored by the number of correctly coded items.	Day 1 through Year 2
Measure of Disability: Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis (FSIQ-RMS)	The FSIQ-RMS is a questionnaire to assess fatigue-related symptoms in patients with RMS. Participants will indicate the severity of fatigue experienced for each question that examines different aspects of fatigue.	Day 1 through Year 2
Number of new and enlarging T2 lesions and Gd-enhancing T1 Lesions	Measured in the brain by Magnetic Residence Imaging (MRI)	Day 1 through Year 2
Plasma Pharmacokinetics (PK) of YTB323 - CMAX	Measured by Cmax - The maximum plasma concentration of YTB323	Day 1 through Year 2
Plasma Pharmacokinetics (PK) of YTB323 - AUC	Measured by AUC - Area under the curve of YTB323	Day 1 through Year 2
Plasma Pharmacokinetics (PK) of YTB323 - Tmax	Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of YTB323	Day 1 through Year 2
Plasma Pharmacokinetics (PK) of YTB323 - Clast	Clast is defined as the Last observed (quantifiable) plasma concentration (Clast)	Day 1 through Year 2
Plasma Pharmacokinetics (PK) of YTB323 - Tlast	Tlast is defined as Time of Last Measurable Concentration	Day 1 through Year 2
Humoral Immunogenicity of YTB323	Incidence and prevalence of pre-existing and treatment induced humoral immunogenicity of YTB323	Day 1 through Year 2
Cellular Immunogenicity of YTB323	Incidence and prevalence of pre-existing and treatment induced cellular immunogenicity of YTB323	Day 1 through Year 2
Safety data including dose limiting toxicities (DLTs), Adverse Events (AEs), and Serious Adverse Events (SAEs) from each dose level	Safety data from each dose level will be used to assess safe dose-level(s) to be continued in phase 2 and later clinical studies	Day 1 through Year 2

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2025
• Primary Completion (Estimated): August 7, 2030
• Study Completion (Estimated): August 7, 2030

Study Registration Dates

• First Submitted: September 26, 2024
• First Submitted That Met QC Criteria: September 26, 2024
• First Posted (Actual): September 27, 2024

Study Record Updates

• Last Update Posted (Actual): September 2, 2026
• Last Update Submitted That Met QC Criteria: September 1, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Relapsing Multiple Sclerosis; MS; CAR-T; RMS; Chimeric Antigen Receptor T cells; YTB323; breakthrough disease activity during previous treatment with a highly efficacious therapy; BD-HET
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis
• Other Study ID Numbers: CYTB323N12101; 2024-512714-18 (Other Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No